We study Salmonella-host interactions and have shown that the mammalian inflammasome, an innate immune protective complex that mediates a pro-inflammatory host response, is important for controlling S. typhimurium infection. The long-term goal of this research application is to understand how the host recognizes intracellular S. typhimurium and how this pathogen has evolved to subvert innate immune defenses. We have demonstrated that multiple host cytosolic sensors are involved in recognizing intracellular S. typhimurium and activating the inflammasome. In addition, we have shown that multiple caspase-1 complexes are formed in response to intracellular S. typhimurium. In Aim1, we will use genetic and biochemical approaches to identify new host molecules and pathways involved in caspase- 1-dependent maturation and release of pro-inflammatory cytokines. In Aim 2, we will take biochemical and genetic approaches to identify host molecules and pathways involved in caspase-1-induced macrophage death. In Aim 3, we will characterize the spatial and temporal relationships between caspase-1 complex formation, cytokine release and host cell death. These studies are aimed at gaining a better understanding of the molecular mechanisms of intracellular recognition, which will lead to the rational design of therapeutics that will benefit public health. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because an increased understanding of the mechanisms that lead to the activation of the inflammasome when our immune system recognizes intracellular bacterial pathogens, such as Salmonella, will lead to novel therapeutic avenues. Thus, the proposed research is relevant to NIH's mission that pertains to developing fundamental knowledge that will reduce the burdens of human infectious disease.